Amyloid protein fibrils are associated with a group of devastating human diseases. The precise etiologic agents for these medical conditions remain undefined, but in several cases appear to be protein fibrils or pre-fibrillar oligomers. Currently there is no approved therapeutic agent that regulates the formation of amyloid fibrils and reverses the symptoms. Our working hypothesis is that interfering with amyloid fibrillation and oligomerization is of clinical benefit to patients suffering from Alzheimer's and other amyloid diseases. Amyloid proteins lack common sequence motifs; nevertheless, they display similar biophysical characteristics and a common 'cross-B spine' structure. The first fully objective atomic model of the common B-spine structure of a fibril-forming peptide was determined in our lab, and additional structures are already available. Based on these atomic structures, we are able to design inhibitors. Our recently designed peptide inhibitors of tau fibrils, based on the structure of the amyloid spines of the tau protein determined in our lab, interfere with fibrillation of tau. We plan to improve the bioavailability and potency of these inhibitors and to design similar peptide inhibitors against Amyloid-beta (AB) fibrils. In recent years several compounds were shown by others to inhibit fibrillation, although the molecular mechanism of this interference is not yet clear. We will determine crystal structures of the fibrils bound to various inhibitors that will advance our understanding of the mechanism of inhibition of fibrils and small oligomers by small molecule inhibitors. The structure determination will be coupled to a computational approach to detect non-toxic, specific and potent inhibitors that will cross the blood-brain-barrier and will bind strongly to fibrils and oligomers. Another important application of this study is to find compounds that could be useful as markers for fibrils in biochemical assays as well as in the diagnosis of fibrils in-vivo. Our project is consistent with the aims of The Therapeutic Imperative, and our proposal involves dose collaboration with members of the ADRC community.